1. 1 Review of the Design and Initial Findings for Pre-specified Outcomes and Subgroups Paul K. Whelton, M.D., M.Sc. Loyola University Medical Center Maywood, Illinois, U.S.A. ALLHAT Revisited How have the Initial Findings Held Up Five Years Later? ALLHAT

2. 2 BP Trial Primary End Points: -Fatal CHD & Non-Fatal MI BP Trial Secondary End Points: -All-cause mortality -Stroke -Combined CHD –Fatal CHD, non-fatal MI, coronary revascularization, hospitalized angina -Combined CVD – combined CHD, stroke, lower extremity revascularization, treated angina, fatal / hospitalized / treated heart failure (HF), hospitalized or outpatient peripheral arterial disease (PAD) -Other – renal (reciprocal serum creatinine, ESRD, estimated GFR) and cancer Predefined Subgroups -Age (<65 y; 65+y) -Gender -Race (Black; Non-Black) -Diabetes (Diabetic; Non-Diabetic) ALLHAT

3. 3 33 CANADA Quebec Ontario Washington Oregon Quebec California MEXICO Nevada Idaho Montana North Dakota South Dakota Wyoming Utah Colorado Arizona New Mexico Texas Oklahoma Kansas Nebraska Minnesota Iowa Wisconsin Michigan Illinois Missouri Indiana Arkansas Louisiana Mississippi Alabama Georgia Tennessee Kentucky Ohio WV Virginia N. Carolina S. Carolina Pennsylvania DE NJ MD New York VT NH CT MA RI Maine New Brunswick Nova Scotia Prince Edward Island Island of New Foundland Puerto Rico (Area Enlarged) St. Croix, Virgin Islands (Area Enlarged) The Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial Florida CTC, UT Program Office, NHLBI -623 Clinical Centers -USA, Canada, Caribbean -Diverse practice settings -Primary sponsor: NIH-NHLBI -Concurrent support from the VA -Assistance from pharmaceutical companies but no role in scientific conduct of trial

4. 4 Baseline Characteristics (33, 357 Participants) ChlorthalidoneAmlodipine Lisinopril Sample Size Mean age, years 15,255 67 9,048 67 9,054 67 Mean SBP/DBP Mean BMI, kg/m 2 145 / 83 30 145 / 83 30 145 / 83 30 Women, % Black, % 47 35 47 36 46 35 Current smoking, %22 ASCVD, % History of CHD, % Type II diabetes, % 47 26 36 46 24 37 47 25 35 ALLHAT

5. 5 Treatment Regimen Step 1 [Double Blinded]Dose 1 Dose 2 Dose 3 Chlorthalidone 12.5 mg 25 mg Amlodipine 2.5 mg 5 mg 10 mg Lisinopril 20 mg 40 mg Step 2 Reserpine 0.05 mg qd 0.1 mg qd 0.2 mg qd Clonidine 0.1 mg bid 0.2 mg bid 0.3 mg bid Atenolol 25 mg qd 50 mg qd 100 mg qd Step 3 Hydralazine 25 mg bid 50 mg bid 100 mg bid ALLHAT Doses were escalated in an attempt to achieve a BP <140/80 mm Hg

6. 6 Percent Taking Blinded Study Drug or Drug from Same ClassALLHAT Chlorthalidone Amlodipine Lisinopril

7. 7 Mean Systolic and Diastolic BP, by Treatment Group Months of Follow-up mm Hg ALLHAT 70 75 80 85 90 135 140 145 150 ~~~~ Systolic BP Diastolic BP Amlodipine Lisinopril Chlorthalidone Lisinopril Chlorthalidone Amlodipine

8. 8 Biochemical Results Sr. Cholesterol & Potassium ChlorthalidoneAmlodipineLisinopril Serum cholesterol- mg/dL Baseline216.1 (43.8)216.5 (44.1)215.6 (42.4) 4 Years197.2 (42.1)195.6 (41.0)*195.0 (40.6)* Serum potassium – mmol/L Baseline4.3 (0.7) 4.4 (0.7)* 4 Years4.1 (0.7)4.4 (0.7)*4.5 (0.7)* * p<.05 compared to chlorthalidone † Ann Intern Med. 1999;130:461-470 ALLHAT JAMA 2002;288:2981-97

9. 9 Biochemical Results Fasting Glucose ChlorthalidoneAmlodipineLisinopril All Participants Baseline123.5 (58.3)123.1 (57.0)122.9 (56.1) 4 Years126.3 (55.6)123.7 (52.0)121.5 (51.3)* Participants with Baseline <126 mg/dL Baseline93.1 (11.7)93.0 (11.4)93.3 (11.8) 4 Years104.4 (28.5)103.1 (27.7)100.5 (19.5)* Diabetes Incidence (fasting glucose  126 mg/dL during follow-up) 4 Years11.6%9.8%*8.1%* *p<.05 compared to chlorthalidone ALLHAT JAMA 2002;288:2981-97

10. 10 Amlodipine / ChlorthalidoneLisinopril / Chlorthalidone CHD0.98 (0.91, 1.08)0.99 (0.91, 1.08) Death0.96 (0.89, 1.02)1.00 (0.94, 1.08) CCHD1.00 (0.94, 1.07)1.05 (0.98, 1.11) Stroke0.93 (0.82, 1.06)1.15 (1.02, 1.30) CCVD1.04 (0.99, 1.09)1.10 (1.05, 1.16) HF1.38 (1.25, 1.52)1.19 (1.07, 1.31) Summary of Outcomes Relative Risks (95% CI) ALLHAT JAMA 2002;288:2981-97

11. 11 Stroke, by Treatment Group. RR (95% CI) in Predefined Subgroups ALLHAT P =.01 for interaction Amlodipine/Chlorthalidone Lisinopril/Chlorthalidone

12. 12 Summary ALLHAT BP Trial Design and Initial Findings 5 y efficacy trial of antihypertensive drug regimens in 42,418 participants. Regimens designed to be similar except for double blinded treatment with chlorthalidone (C), amlodipine (A), lisinopril (L) or doxazosin Doxazosin comparison stopped prematurely due to difference in CVD events Baseline characteristics similar in 33,357 C, A and L participants Strong representation of important subgroups Excellent adherence to assigned study drugs The three regimens differed slightly but significantly in BP control, Sr. Cholesterol, Sr. Potassium and fasting blood sugar No difference in the primary outcome for C vs. A or C vs. L C was better than A for HF C was better than L for stroke, combined CVD events and HF. There was a significant C vs. L treatment X race interaction for the stroke outcome. The ALLHAT findings suggest thiazide-type diuretics are the preferred first-step antihypertensive drug therapy unless there is a contraindication to their use